The patient has secondary amenorrhea with low levels of estradiol and gonadotropins. This clinical picture is most consistent with hypothalamic amenorrhea, which sometimes occurs in women who exercise excessively or who have stressful jobs. The disorder results from reduced frequency of gonadotropin-releasing hormone (GnRH) pulses in the hypothalamus. Treatment consists of stress management and, if menses do not resume, estrogen replacement therapy (see Chapter 48).

3. A nulliparous 48-year-old woman presents with symptoms of thyrotoxicosis. She has a modest, nontender goiter and no exophthalmos. She takes no medications and has had no recent radiology procedures. The following results are found on thyroid evaluation: free T4 = 3.5 ng/dL (nL, 0.7-2.7), TSH < 0.1 mU/L, 24-hour radioactive iodine uptake (RAIU) = 1% (nL, 20-35%), thyroglobulin = 35 ng/mL (nL, 2-20), and sedimentation rate = 10 mm/h. What is the likely diagnosis?

The patient has clinical and biochemical thyrotoxicosis but the RAIU is low. The differential diagnosis includes postpartum thyroiditis, silent thyroiditis, subacute thyroiditis, factitious thyrotoxicosis, and iodine-induced thyrotoxicosis. She has never been pregnant and denies medication use and recent iodine exposure. The nontender gland, elevated thyroglobulin, and normal sedimentation rate are most consistent with silent thyroiditis. A transient (1-3 months) thyrotoxic phase followed by a transient (1-3 months) hypothyroid phase is expected before the condition resolves; 20% of patients, however, remain hypothyroid. If symptomatic, the thyrotoxic phase is best treated with beta blockers and the hypothyroid phase can be managed, if necessary, with levothyroxine (see Chapter 36).

Significant elevations of total cholesterol and LDL cholesterol, normal TG, tendon xanthomas, and premature coronary artery disease are most consistent with a diagnosis of heterozygous familial hypercholesterolemia. This disorder is due to deficient or abnormal LDL receptors or an abnormal apoprotein B-100 molecule. Aggressive lipid lowering with combinations of statins, ezetimibe, bile acid resins and/or niacin, and occasionally plasmapheresis is indicated (see Chapter 7).

5. A 28-year-old man presents because of infertility. He is found to have small, firm testes and gynecomastia. Laboratory testing shows the following abnormalities: testosterone = 2.6 ng/mL (nL, 3.0-10.0), LH = 88 mIU/mL (nL, 2-12), and FSH = 95 mIU/mL (nL, 2-12). What is the likely diagnosis?

The patient has hypergonadotropic hypogonadism with small firm testes and gynecomastia, which is most consistent with a diagnosis of Klinefelter's syndrome. Such patients usually have a 47XXY karyotype. Androgen replacement therapy is the treatment of choice (see Chapter 45).

The patient has hyperinsulinemic hypoglycemia. The differential diagnosis includes insulinoma, surreptitious insulin injection, and oral sulfonylurea ingestion. The elevated serum C-peptide and proinsulin levels are most consistent with an insulinoma. After an appropriate localizing procedure, surgical removal is the treatment of choice (see Chapters 6 and 55).

The patient has secondary amenorrhea with low levels of estradiol and elevated gonadotropins. The differential diagnosis includes premature ovarian failure and the resistant ovary syndrome. In a patient with another autoimmune disease (type 1 diabetes mellitus), the most likely diagnosis is premature ovarian failure. Hormone replacement therapy is the treatment of choice (see Chapter 48).

The patient has moderately increased serum prolactin levels, pituitary enlargement, and severe primary hypothyroidism. Her entire clinical picture is most likely explained solely by the hypothyroidism, which is well known to cause secondary hypersecretion of prolactin and pituitary enlargement due to thyrotroph hyperplasia. All abnormalities should resolve after adequate thyroid hormone replacement is established (see Chapters 21 and 49).

9. A 6-year-old girl has recently developed breast enlargement and some pubic hair. She has not complained of headaches and has had good health otherwise. Her older sister entered puberty at about 8 years of age. Her height is at the 90th percentile for her age, and her physical examination reveals Tanner stage 3 breast development and stage 2 pubic hair growth. Abdominal and pelvic examinations are normal. Laboratory tests show the following results: LH = 7 mIU/mL (nL, 2-15), FSH = 8 mIU/mL (nL, 2-20), prolactin = 6 ng/mL (nL, 2-25), TSH = 1.9 mU/L (nL, 0.5-5.0), and a normal pituitary MRI scan. Her bone age is 1.8 years ahead of the chronologic age. What is the probable diagnosis?

The patient has gonadotropin-dependent true precocious puberty. The etiology includes pituitary and hypothalamic tumors, but most cases in girls are idiopathic. The normal pituitary MRI points to a diagnosis of idiopathic precocious puberty. A long-acting GnRH analog should successfully arrest her premature development and allow her to enter puberty at a later, more appropriate time (see Chapter 44).

10. A 19-year-old man presents with excessive thirst and urination. Laboratory evaluation shows the following: serum glucose = 88 mg/dL, serum sodium = 146 mEq/L, serum osmolality = 298 mOsm/kg, and urine volume = 8800 mL/24 h. A water deprivation test is performed, and it shows a urine osmolality of 90 mOsm/kg with no response to water deprivation and an increase in urine osmolality to 180 mOsm/kg after the administration of vasopressin. What is the likely diagnosis?

The patient has polyuria and polydipsia with maximally dilute urine. The differential diagnosis includes central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia. The lack of response to water deprivation and the more than 50% increase in urine osmolality after administration of vasopressin are most consistent with central diabetes insipidus. This may be caused by inflammatory or mass lesions in the hypothalamus but is often idiopathic. An MRI of the pituitary-hypothalamic region should be performed. The treatment of choice is desmopressin (DDAVP) nasal spray (see Chapter 28).

Cushingoid features and elevated urinary excretion of cortisol confirm the diagnosis of Cushing's syndrome. The cause is usually an ACTH-secreting pituitary adenoma (65-80%), ectopic production of ACTH (10-15%), or a cortisol-producing adrenal adenoma (10-15%). The normal plasma level of ACTH, which is inappropriate for the elevated serum cortisol level, and suppression of serum cortisol with high-dose dexamethasone are most consistent with a pituitary adenoma (Cushing's disease). This should be confirmed with an MRI of the pituitary gland and/or inferior petrosal sinus sampling. Transsphenoidal surgical removal is the treatment of choice (see Chapter 24).

Hypocalcemia, hyperphosphatemia, and a low serum PTH level are diagnostic of primary hypoparathyroidism. This disorder, which is often autoimmune in nature, may occur in association with adrenal insufficiency as part of the polyendocrine failure type I syndrome. The treatment of this condition is calcium supplementation along with calcitriol administration. Calcitriol is necessary because the lack of PTH makes these patients unable to convert 25 hydroxyvitamin D into 1,25 dihydroxyvitamin D in the kidneys and the latter vitamin D metabolite is necessary for normal intestinal calcium absorption (see Chapters 17 and 54).

The patient has elevations of both serum cholesterol and TG and no detected disorders that cause secondary dyslipidemia. The differential diagnosis includes familial combined hyperlipidemia and familial dysbetalipoproteinemia. The elevated level of apoprotein B and the normal apoprotein E phenotype are most consistent with familial combined hyperlipidemia. The top treatment priority is LDL reduction with a statin. Once LDL cholesterol is under the NCEP goal, persistent TG elevations should be addressed with the possible addition of a fibrate or niacin (see Chapter 7).

14. A 58-year-old man has recently developed diabetes mellitus, weight loss, and a skin rash that is most prominent on the buttocks; a dermatologist diagnoses this as necrolytic migratory erythema. What is the probable underlying diagnosis?

Diabetes mellitus, weight loss, and necrolytic migratory erythema are virtually diagnostic of a glucagon-secreting pancreatic endocrine tumor (glucagonoma). The diagnosis can be confirmed by finding an elevated serum level of glucagon. After appropriate localizing procedures, surgery is the treatment of choice, if possible. Chemotherapy should be considered for unresectable malignant tumors or tumor remnants (see Chapter 55).

The vast majority of patients with hypercalcemia and a mildly elevated serum PTH level have hyperparathyroidism. But here, the very low urinary calcium excretion and family history of unsuccessful parathyroidectomies point to a likely diagnosis of familial hypocalciuric hypercalcemia. The diagnosis is confirmed by finding a calcium/creatinine clearance ratio (urine calcium × serum creatinine/serum calcium × urine creatinine) of < 0.01. This autosomal dominant disorder results from a heterozygous inactivating mutation in the gene that encodes the calcium receptor. The mutant receptors, present in parathyroid and renal tubular cells, have a raised threshold for calcium recognition. The result is a physiologic equilibrium, in which hypercalcemia coexists with mild elevations of PTH and low urinary calcium excretion. The disorder causes no morbidity and does not require treatment (see Chapters 14 and 15).

The very low T3, mildly low T4, elevated T3 resin uptake, and normal TSH are most consistent with the euthyroid sick syndrome. This is not a primary thyroid disorder but is instead a set of circulating thyroid hormone abnormalities that occur in the presence of nonthyroidal illnesses; it corrects when the underlying illness resolves. Treatment of the condition with thyroid hormone administration, though controversial, is not currently recommended (see Chapter 40).

Primary amenorrhea, short stature, a low serum estradiol level, and elevated gonadotropins are most consistent with a diagnosis of Turner's syndrome. This disorder, which is characterized by ovarian dysgenesis, is associated with a 45XO karyotype. These patients should be given hormone replacement therapy with estrogen and progesterone. GH therapy should also be considered as it has been shown to improve longitudinal growth and final height (see Chapter 48).

Hypercalcemia, hypophosphatemia, and elevated serum PTH levels are characteristic of primary hyperparathyroidism. The only other cause of hypercalcemia with increased serum PTH levels is familial hypocalciuric hypercalcemia. Hyperparathyroidism is usually due to a solitary parathyroid adenoma, but familial cases and those associated with multiple endocrine neoplasia (MEN) syndromes more often have 4-gland hyperplasia. Surgical indications include serum calcium levels > 1 mg/dL above the normal range, urine calcium > 400 mg/24 h., kidney stones, renal impairment, osteoporosis, or symptoms related to hyperparathyroidism. Observation alone or bisphosphonate therapy may be appropriate for patients with mild, asymptomatic disease, or only mild bone loss (see Chapter 16).

19. A 32-year-old woman presents with the recent onset of fatigue, palpitations, profuse sweating, and emotional lability. She gave birth to her second child 8 weeks ago. Her pulse is 100/minute, and she has mild lid retraction, a fine hand tremor, and a slightly enlarged, nontender thyroid gland. Laboratory tests are as follows: TSH < 0.03 mU/L (nL, 0.5-5.0), free T4 = 3.8 ng/dL (nL, 0.7-2.7), and RAIU is < 1% at 4 and 24 hours. What is the probable diagnosis?

Postpartum thyrotoxicosis is most often due to Graves' disease or postpartum thyroiditis. The RAIU will distinguish the two, being high in Graves' disease and very low in postpartum thyroiditis. This patient has postpartum thyroiditis, a condition caused by lymphocytic inflammation with leakage of thyroid hormone from the inflamed gland. There is often a thyrotoxic phase (lasting 1-3 months) followed by a hypothyroid phase (lasting 1-3 months) and eventual return to euthyroidism, although nearly 20% remain permanently hypothyroid. Treatment consists of beta blockers, if needed, for symptom control in the thyrotoxic phase, and levothyroxine, if needed, for symptom control in the hypothyroid phase and for those who remain permanently hypothyroid (see Chapter 36).

20. A 70-year-old man complains of a 1-year history of weakness, weight loss, and hand tremors. He has been treated with amiodarone for nearly 3 years for a diagnosis of paroxysmal atrial flutter. Laboratory tests show the following: TSH < 0.01 mU/L (nL, 0.5-5.0), free T4 = 3.35 ng/dL (nL, 0.7-2.7), and the RAIU was 2.7% at 6 hours and 4.1% at 24 hours. Thyroid scan showed scant patchy tracer uptake. What is the likely diagnosis?

This man most likely has amiodarone-induced thyrotoxicosis (AIT). This condition occurs in up to 10% of patients using amiodarone, which has very high iodine content. There are two subtypes: type 1 AIT results from iodine overload and occurs mainly in patients with underlying goiters; type 2 AIT results from drug-induced thyroid follicular damage. Both are associated with a low RAIU. There are no tests to reliably distinguish the two subtypes, although an underlying goiter and a detectable RAIU are more common in type 1 AIT. Treatment of type 1 AIT consists of administering thionamides with or without potassium perchlorate, whereas type 2 AIT may respond to steroid therapy. Difficult cases may require plasmapheresis, dialysis, or thyroidectomy (see Chapter 34).

This picture is most consistent with idiopathic hypogonadotropic hypogonadism, also known as Kallmann's syndrome. This disorder is due to a deficiency of GnRH, resulting from failure of fetal migration of the GnRH secreting neurons from the olfactory placode to the hypothalamus. Mutations of the Kal gene have been detected in some patients. Maldevelopment of the olfactory lobe causes the associated anosmia. Androgen therapy is indicated to promote appropriate masculinization. When desired, these patients can also become fertile by receiving treatment with GnRH or gonadotropin preparations (see Chapters 44 and 45).

This patient has a prolactinoma, manifested by impotence, headaches, bitemporal hemianopsia, and a significantly elevated serum prolactin level. Hypercalcemia with an elevated serum PTH level indicates that he also has hyperparathyroidism. The MEN type 1 syndrome (MEN 1), which consists of hyperparathyroidism, pituitary tumors, and pancreatic endocrine tumors, results from an inherited mutation in the menin gene. This patient should be screened for a gastrinoma and insulinoma by measuring serum gastrin, insulin, proinsulin, and glucose following an overnight fast. After pituitary imaging studies, he should be treated with a dopamine agonist and/or transsphenoidal surgery, and subsequently parathyroid surgery (see Chapters 21 and 53).

This patient has central hypothyroidism due to pituitary damage from the combined effects of surgery and radiation treatment of her pituitary tumor 10 years earlier. Such a lengthy delay in the development of this condition is not uncommon. The diagnosis of central hypothyroidism is based on the presence of symptoms of thyroid hormone deficiency, a low serum free T4 and a low or low-normal serum TSH. Treatment consists of levothyroxine replacement in doses sufficient to relieve symptoms and to maintain the serum free T4 level in the mid-normal or upper-normal range. Because TSH secretion is impaired, the serum TSH level cannot be used to monitor this patient's response to therapy. Assessment of her pituitary-adrenal axis is also indicated (see Chapters 19 and 35).

24. A 32-year-old woman complains of deep pain in both thighs. She was diagnosed as having type 1 diabetes mellitus at age 20. She currently has 2-3 bowel movements each day. Her menses are regular. Her diet is well balanced with adequate calcium intake and she takes a multivitamin. Physical examination is normal. Laboratory studies show the following: serum calcium = 8.2 mg/dL (nL, 8.5-10.5), phosphorous = 2.3 ng/dL (nL, 2.5-4.5), alkaline phosphatase = 312 U/L (nL, 25-125), PTH = 155 pg/mL (nL, 11-54), and 25 hydroxyvitamin D = 7 ng/mL (nL, 16-74). Explain the findings in this patient and suggest a probable underlying diagnosis.

Her biochemical profile of hypocalcemia, hypophosphatemia, elevated alkaline phosphatase, and significant secondary hyperparathyroidism suggests vitamin D deficiency, which is confirmed by the low serum 25-hydroxyvitamin D level. Lactose intolerance can cause chronic diarrhea but seldom results in vitamin D and calcium malabsorption. Celiac disease (gluten sensitive enteropathy), which occurs with increased frequency in patients with type 1 diabetes mellitus, should be suspected. The diagnosis can be confirmed by the measurement of tissue transglutaminase, antiendomysial or antigliadin antibodies, or by a small bowel biopsy. The treatment is elimination of gluten (wheat, rye, barley, and oats) from the diet and supplementation with calcium and vitamin D (see Chapter 12).

25. A 42-year-old man presents for evaluation of a skin rash that has recently developed. He has known type 2 diabetes mellitus. He drinks 2-3 alcoholic beverages several nights each week. Physical examination shows eruptive xanthomas (red papules with golden crowns) all over his body, most prominently on the buttocks, thighs, and forearms. Laboratory studies reveal the following: glucose = 310 mg/dL, hemoglobin A1C (HbA1C) = 12.9%, cholesterol = 1082 mg/dL, and TG = 8900 mg/dL. Discuss the cause and treatment of this lipid disorder.

The patient has severely elevated serum TG. This condition usually results from combining a secondary cause of TG elevation (uncontrolled diabetes mellitus, excess alcohol use) with an inherited TG disorder (familial hypertriglyceridemia or familial combined hyperlipidemia). His LDL cholesterol cannot be assessed until the serum TG levels are < 400 mg/dL. Because he is at high risk of developing acute pancreatitis, the priority is to quickly lower his serum TG level to less than 1000 mg/dL. This goal can be achieved most effectively with a temporary very low fat (< 5% fat) diet, blood glucose control, and discontinuation of alcohol. TG levels will fall by about 20% a day on this regimen. Fenofibrate or gemfibrozil should then be added and he should be switched to an American Heart Association diet. Diabetes control must be continued and further alcohol intake should be discouraged (see Chapter 7).

26. A 26-year-old woman requests to be tested for a type of thyroid cancer that has recently been found in her mother and two of five siblings. She notes that she has had intermittent headaches and palpitations for the past year. Her blood pressure is 164/102. She has a 1-cm, left-sided thyroid nodule without associated lymphadenopathy. Laboratory testing shows the following results: serum calcium = 11.2 mg/dL (nL, 8.5-10.5), phosphorus = 2.4 mg/dL (nL, 2.5-4.5), albumin = 4.5 g/dL (nL, 3.2-5.5), intact PTH = 55 pg/mL (nL, 11-54), calcitonin = 480 pg/mL (nL, 0-20), and 24-hour urine catecholamines = 1225 μg (nL, 0-200). Discuss her diagnosis and management.

The thyroid nodule, elevated serum calcitonin, and family history make medullary thyroid cancer likely. Her hypertension, headaches, palpitations, and elevated urinary catecholamines indicate a probable pheochromocytoma. She also has hyperparathyroidism. MEN type 2A (MEN 2A) consists of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. It is an autosomal dominant syndrome that results from a germline mutation in the Ret gene. After alpha blocker administration and blood pressure control, treatment of this patient would consist of removal of the pheochromocytoma(s) followed by later removal of the abnormal thyroid and parathyroid glands. Screening at-risk family members for the Ret/MCT oncogene should also be done (see Chapters 38 and 53).

27. A 68-year-old man complains of a 10-year history of progressive pain in the shins, knees, and left arm. He also notes progressive hearing loss. Physical examination reveals tenderness above the left elbow and enlarged, bowed shins. Bone scan shows intense uptake in both tibias and the left humerus. Skeletal x-rays show enlargement with multiple focal lytic and sclerotic areas in the tibias and the distal left humerus. Laboratory evaluation reveals: serum calcium = 9.8 mg/dL (nL, 8.5-10.5) and alkaline phosphatase = 966 U/L (nL, 25-125). What is the probable diagnosis?

Bone pain and deformity, reduced hearing, and markedly elevated serum alkaline phosphatase levels suggest a diagnosis of Paget's disease. Intense radioisotope uptake on bone scanning supports this diagnosis and the characteristic findings on skeletal radiographs confirm it. Treatment options include analgesics, intermittent oral or intravenous bisphosphonates, and calcitonin, all of which may control but will not cure the disease (see Chapter 13).

28. A 19-year-old man has experienced fatigue, muscle weakness, and dizziness for the past 3 weeks. This morning he fainted when he went outdoors to exercise. His blood pressure is 95/60, and his pulse is 110. His skin is cool, dry, and tanned. His thyroid feels normal. Laboratory testing shows the following: hematocrit = 36%, glucose = 62 mg/dL, sodium = 120 mEq/L, potassium = 6.7 mEq/L, creatinine = 1.4 mg/dL, and blood urea nitrogen (BUN) = 36 mg/dL. What endocrine disorder should be considered and evaluated?

Hyponatremia with hyperkalemia always suggests adrenal insufficiency (Addison's disease). Fatigue, weakness, hypotension, tanned skin, anemia, azotemia, and hypoglycemia are also consistent with this diagnosis. The most common cause is autoimmune destruction of the adrenal glands. The diagnosis is made by a Cosyntropin stimulation test that shows a low basal serum cortisol level that fails to increase after ACTH administration. During an adrenal crisis, however, one does not have time to wait for the test results. When this diagnosis is suspected, one should draw blood for a serum cortisol measurement and then start treatment with intravenous fluids and glucocorticoids (hydrocortisone, 100 mg every 6 hours). Precipitating conditions should be actively sought and treated. Once the patient is stable, he can be switched to oral hydrocortisone and Florinef for chronic maintenance. The diagnosis is likely if the serum cortisol measured during the crisis was low but this should be confirmed by repeat Cosyntropin stimulation testing upon recovery from the acute event (see Chapter 31).

The presence of hypertension and hypokalemia suggests primary aldosteronism (Conn's syndrome). The PA level is elevated, the PR is suppressed, and the PA/PR ratio is greater than 20, supporting this diagnosis. It is confirmed by the failure of PA to suppress after volume expansion with saline. The next step is to determine if the cause is an aldosterone-producing adenoma or bilateral adrenal hyperplasia. The very low basal serum potassium, the drop in PA during the 4-hour posture test, and the elevated 18-hydroxycorticosterone level are consistent with an adrenal adenoma. An abdominal computed tomography (CT) scan should be done next. The treatment for an aldosterone-producing adrenal adenoma is surgical removal. Spironolactone should be given to control blood pressure and to normalize the serum potassium preoperatively (see Chapter 28).